1. Field of the Invention
This invention relates to selected esters of unsymmetrically 2-substituted glycolic acid dimers, their use for the preparation of unsymmetrically 3,6-substituted 1,4-dioxane-2,5-diones and a process for their preparation.
2. Technical Review
Selected esters of unsymmetrically 2-substituted glycolic acid dimers of the general structure: ##STR1## wherein R.sup.1, R.sup.2, R.sup.3, and R.sup.4 are selected from the group consisting of H, alkyl, aryl, alkaryl and aralkyl which may include branched chain, unsaturated chain, halogen, nitrile, ketone, and ether substitutions, provided that R.sup.1 and R.sup.2 are not equal to R.sup.3 and R.sup.4 ; and, R.sup.5 is selected from the group consisting of alkyl, aryl, alkaryl and aralkyl which may include branched chain, unsaturated chain, halogen, nitrile, and ether substitutions, hereinafter designated as Formula Ia, have been disclosed. While in all of the prior art compounds the pKa of the equivalent alcohol of R.sup.5 is greater then 15.5, the compounds claimed in the present invention, hereinafter designated as Formula I, differ from previously disclosed compounds in that the pKa of the equivalent alcohol of R.sup.5 is 14.5 or less.
The compounds of the present invention also differ in structure from certain previously disclosed esters of unsymmetrically 2-substituted glycolic acid dimers in that the utility of these previously disclosed dimers resides in a pharmacologically or agriculturally active side group whose activity is modified by the presence of the dimer acid moiety. (See U.S. Pat. No. 4,533,659, U.S. Pat. No. 4,609,650, U.S. Pat. No. 4,663,659, U.S. Pat. No. 4,778,809, and JP 50071695) or in a specific use for synthetic organic chemistry, Tetrahedron Lett., 52, 5497-5500 (1982) and Syn. Comm., 18, 2337-2348 (1988).)
Two methods of preparing 2-substituted glycolic acid dimers of Formula Ia are known:
(1) U.S. Pat. No. 4,609,650 discloses the production of selected esters of unsymmetrically 2-substituted glycolic acid dimers (e.g. Formula Ia where R.sup.1 =R.sup.3 =R.sup.4 =H, R.sup.2 =CH.sub.2 CH(CH.sub.3).sub.2, and R.sup.5 =a steroid derivative) by reaction of an .alpha.-hydroxy carboxylate anion with an ester of an .alpha.-halocarboxylic acid derivative. This method suffers from the disadvantage that derivatives of (.alpha.-halocarboxylic acid are not readily available commercially and usually must be prepared.
(2) Tetrahedron Letters, 5, 309-312, (1975), provides an ester of an unsymmetrically 2-substituted glycolic acid dimer (Formula Ia where R.sup.1 =R.sup.2 =R.sup.3 =H, R.sup.4 =CH.sub.2 Ph, and R.sup.5 =CH.sub.3) by condensation of an .alpha.-hydroxy ester derivative with an acid halide derivative bearing a protected hydroxy group. This method is disadvantageous because it requires protection of one of the alcohol moieties, activation of one of the carboxyl groups prior to condensation, and deprotection following condensation.
There is a need for a method for the preparation of esters of unsymmetrically 2-substituted glycolic acid dimers which overcomes the limitations of the described available methods. A method possessing these attributes would be one based on the direct condensation of a mixture of monomers consisting of a compound of Formula III and a compound of Formula IV, as shown in Equation 1, wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4 and R.sup.5 are as defined on page 1 and R.sup.6 is selected from the group including aryl, alkyl, and aralkyl with optional branched chain, halogen, nitrile and ether substitutions. ##STR2## Such a reaction can be catalyzed nonenzymatically (e.g. chemically, by acid or base). However, since both monomers are bifunctional and can act as acyl donor and nucleophile, the expected result would be a mixture of four possible dimers and higher oligomers. For example, if the monomers III and IV are 2-chloroethyl lactate and methyl glycolate, respectively, then the expected dimers would be 2-methoxy-2-oxoethyl lactate, 2-[2-chloroethoxy]-1-methyl-2-oxoethyl lactate, 2-methoxy 2-oxoethyl glycolate and 2-chloroethyl 2-(2-hydroxy-1-oxoethoxy)propionate. Also, higher oligomers would arise from further reaction. Since the relative reactivities of the substrate monomers as acyl donor and as nucleophile is determined by their structure, some degree of selectivity can be achieved when one monomer is a better acyl donor and/or a poorer nucleophile as compared to the other monomer. In practice, high selectivity is difficult to achieve using chemical catalysts and so mixtures are obtained. As such mixtures are difficult to purify, such chemically catalyzed methods, are of limited value.
In contrast to the above described chemical method, a process relying on enzyme catalyzed transesterification of monomer III and monomer IV is much more likely than the above described chemical methods to selectively produce a compound of Formula Ia because the specificity of enzymes toward their substrates is unparalleled by chemical catalysts. In the example cited above, for example, an enzyme catalyzed reaction of 2-chloroethyl lactate and methyl glycolate produces 2-methoxy-2-oxoethyl lactate and no other dimer species or higher oligomer. Thus, a process relying on enzymatic transesterification of monomer III and monomer IV to selectively produce a compound of Formula Ia overcomes the problems inherent in methods utilizing traditional chemical catalysts and offers an attractive alternative to disclosed methods.
The use of enzymes in organic synthesis to effect transesterifications is well documented. For example, the use of lipases has been directed toward resolution of chiral carboxylic acids or alcohols in esterification or transesterification reactions. Angew. Chem. Int. Ed. Engl., 28, 695-707 (1989). Enzyme Microb. Technol. 11, 194-211, (1989).
Enzyme catalyzed reactions of hydroxy-carboxylate esters have been disclosed, however, these reactions have been limited to polymerizations or lactonizations of single substrates. For example, lipase catalyzed formation of lactones or dilactones from .omega.-hydroxycarboxylic acids and esters or hydroxycarboxylate esters containing secondary alcohols has been described. Annals N. Y. Acad. Sci. 434, 569 (1984); Tetrahedron Lett. 28, 805 (1987); Tetrahedron Lett. 28, 3861 (1987); J. Org. Chem. 54, 4263 (1989). Lipase and protease catalyzed formation of oligomers from carboxylic acids and esters containing a hydroxyl substitution has also been described. Biotechnol. Lett. 7, 303 (1985); Tetrahedron Lett. 28, 5367 (1987); Chem Express 3, 135 (1988); J. Org. Chem. 54, 5645 (1989); Wallace et. al., 198th ACS National Meeting, Miami Beach, Fla., Division of Microbial and Biochemical Technology, Abstract #91.
The enzyme catalyzed reaction of a mixture of dissimilar hydroxycarboxylate esters has not been disclosed in the prior art. Furthermore, the enzyme catalyzed synthesis of unsymmetrically substituted glycolic acid dimer esters has not been disclosed. Indeed, the prior art teaches away from the use of enzymes for the synthesis of unsymmetrically substituted glycolic acid dimer esters by disclosing that, in the presence of enzymes, glycolic acid dimer esters are cleaved by hydrolysis. Synth. Commun. 18, 2337-2348 (1988); Tetrahedron Lett., 5, 309-312 (1975).
One aspect of the present invention is the use of compounds of Formula Ia as precursors to unsymmetrically 3,6-substituted 1,4-dioxane-2,5-diones of Formula II. The reaction is illustrated in Equation 1: ##STR3## None of the above mentioned disclosures have taught that compounds of Formula Ia are useful for the preparation of unsymmetrically 3,6-substituted 1,4-dioxane-2,5-diones, represented by Formula II.